Moving towards effective therapeutic strategies for Neuronal Ceroid Lipofuscinosis

Orphanet Journal of Rare Diseases

Volumn 11, Issue 1, 2016, Pages

  Geraets, Ryan D ^a,b   Koh, Seung Yon ^a   Hastings, Michelle L ^c   Kielian, Tammy ^d   Pearce, David A ^a,b   Weimer, Jill M ^a,b  

^a SANFORD RESEARCH   (United States)

^b UNIVERSITY OF SOUTH DAKOTA   (United States)

^c ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE   (United States)

^d UNIVERSITY OF NEBRASKA MEDICAL CENTER   (United States)

Author keywords

Antisense oligonucleotides; Autophagy modulators; Batten disease; Enzyme replacement therapy; Gene therapy; Lysosomal modulators; Palmitoyl Protein Thioesterase 1; RNA modulating therapies; Stem cell therapy; Translational research; Tripeptidyl peptidase 1

Indexed keywords

ALPHA TOCOPHEROL; ANTIINFLAMMATORY AGENT; ANTIOXIDANT; ATALUREN; CURCUMIN; FENTANYL; LAMOTRIGINE; LIPOSOME; MELATONIN; MYCOPHENOLATE MOFETIL; NANOCARRIER; SELENIUM; TRIPEPTIDYL PEPTIDASE I; AMINOPEPTIDASE; DIPEPTIDYL PEPTIDASE; PALMITOYL-PROTEIN THIOESTERASE; SERINE PROTEINASE; THIOL ESTER HYDROLASE; TRIPEPTIDYL-PEPTIDASE 1;

BONE MARROW TRANSPLANTATION; CLINICAL EFFECTIVENESS; CLINICAL FEATURE; CLINICAL TRIAL (TOPIC); CYSTIC FIBROSIS; DRUG DELIVERY SYSTEM; DRUG RESEARCH; ENZYME REPLACEMENT; EPILEPSY; GENE REPRESSION; GENE THERAPY; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HUMAN; LYSOSOME; MUSCULAR DYSTROPHY; NEURONAL CEROID LIPOFUSCINOSIS; PAIN; PATIENT CARE; REVIEW; SLEEP DISORDER; UMBILICAL CORD BLOOD; GENETICS; METABOLISM;

AMINOPEPTIDASES; DIPEPTIDYL-PEPTIDASES AND TRIPEPTIDYL-PEPTIDASES; HUMANS; NEURONAL CEROID-LIPOFUSCINOSES; SERINE PROTEASES; THIOLESTER HYDROLASES;

EID: 84966440677     PISSN: None     EISSN: 17501172     Source Type: Journal    
DOI: 10.1186/s13023-016-0414-2     Document Type: Review

References (185)

1. Wang RY et al. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Genet Med. 2011;13(5):457-84.
2. Meikle PJ et al. Prevalence of lysosomal storage disorders. JAMA. 1999;281(3):249-54.
3. Williams RE, Mole SE. New nomenclature and classification scheme for the neuronal ceroid lipofuscinoses. Neurology. 2012;79(2):183-91.
4. Mink JW et al. Classification and natural history of the neuronal ceroid lipofuscinoses. J Child Neurol. 2013;28(9):1101-5.
5. Cooper JD. Moving towards therapies for juvenile Batten disease? Exp Neurol. 2008;211(2):329-31.
6. Sondhi D et al. Advances in the treatment of neuronal ceroid lipofuscinosis. Expert Opin Orphan Drugs. 2013;1(12):951-75.
7. Chabrol B, Caillaud C, Minassian B. Neuronal ceroid lipofuscinoses. Handb Clin Neurol. 2013;113:1701-6.
8. Boustany R-MN. Lysosomal storage diseases - the horizon exapnds. Nat Rev Neurol. 2013;9:583-98.
9. Bellizzi III JJ, Widom J, Christopher K, Lu J-Y, Das AK, Hofmann SL, Clardy J. The crystal structure of palmitoyl protein thioesterase 1 and the molecular basis of infantile neuronal ceroid lipofuscinosis. Proc Natl Acad Sci U S A. 2000;97(9):4573-8.
10. Mole SE, Williams RE, Goebel HH. Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics. 2005;6(3):107-26.
11. Kousi M, Lehesjoki AE, Mole SE. Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. Hum Mutat. 2012;33(1):42-63.
12. Sleat DE et al. Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis. Science. 1997;277(5333):1802-5.
13. Sohar I et al. Biochemical characterization of a lysosomal protease deficient in classical late infantile neuronal ceroid lipofuscinosis (LINCL) and development of an enzyme-based assay for diagnosis and exclusion of LINCL in human specimens and animal models. J Neurochem. 1999;73(2):700-11.
14. Sleat DE et al. Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder. Am J Hum Genet. 1999;64(6):1511-23.
15. Vines DJ, Warburton MJ. Classical late infantile neuronal ceroid lipofuscinosis fibroblasts are deficient in lysosomal tripeptidyl peptidase I. FEBS Lett. 1999;443(2):131-5.
16. Pontikis CC et al. Late onset neurodegeneration in the Cln3-/- mouse model of juvenile neuronal ceroid lipofuscinosis is preceded by low level glial activation. Brain Res. 2004;1023(2):231-42.
17. Xiong J, Kielian T. Microglia in juvenile neuronal ceroid lipofuscinosis are primed toward a pro-inflammatory phenotype. J Neurochem. 2013;127(2):245-58.
18. Pontikis CC et al. Thalamocortical neuron loss and localized astrocytosis in the Cln3Deltaex7/8 knock-in mouse model of Batten disease. Neurobiol Dis. 2005;20(3):823-36.
19. Aberg L et al. Lamotrigine therapy in infantile neuronal ceroid lipofuscinosis (INCL). Neuropediatrics. 1997;28(1):77-9.
20. Aberg L, Kirveskari E, Santavuori P. Lamotrigine therapy in juvenile neuronal ceroid lipofuscinosis. Epilepsia. 1999;40(6):796-9.
21. Aberg LE et al. Epilepsy and antiepileptic drug therapy in juvenile neuronal ceroid lipofuscinosis. Epilepsia. 2000;41(10):1296-302.
22. Mannerkoski MK et al. Transdermal fentanyl therapy for pains in children with infantile neuronal ceroid lipofuscinosis. Eur J Paediatr Neurol. 2001;5(Suppl A):175-7.
23. Hatonen T et al. Melatonin ineffective in neuronal ceroid lipofuscinosis patients with fragmented or normal motor activity rhythms recorded by wrist actigraphy. Mol Genet Metab. 1999;66(4):401-6.
24. Hatonen T et al. Bright light suppresses melatonin in blind patients with neuronal ceroid-lipofuscinoses. Neurology. 1998;50(5):1445-50.
25. Heikkila E et al. Circadian rhythm studies in neuronal ceroid-lipofuscinosis (NCL). Am J Med Genet. 1995;57(2):229-34.
26. Lonnqvist T et al. Hematopoietic stem cell transplantation in infantile neuronal ceroid lipofuscinosis. Neurology. 2001;57(8):1411-6.
27. Lake BD et al. Bone marrow transplantation in Batten disease (neuronal ceroid-lipofuscinosis). Will it work? Preliminary studies on coculture experiments and on bone marrow transplant in late infantile Batten disease. Am J Med Genet. 1995;57(2):369-73.
28. Lake BD et al. Bone marrow transplantation in late infantile Batten disease and juvenile Batten disease. Neuropediatrics. 1997;28(1):80-1.
29. Yuza Y et al. Allogenic bone marrow transplantation for late-infantile neuronal ceroid lipofuscinosis. Pediatr Int. 2005;47(6):681-3.
30. Naidu S et al. Selenium treatment in neuronal ceroid-lipofuscinosis. Am J Med Genet Suppl. 1988;5:283-9.
31. Gruber K. Europe gives gene therapy the green light. Lancet. 2012;380(9855):e10.
32. Byrne BJ et al. Gene therapy approaches for lysosomal storage disease: next-generation treatment. Hum Gene Ther. 2012;23(8):808-15.
33. Weinberg MS, Samulski RJ, McCown TJ. Adeno-associated virus (AAV) gene therapy for neurological disease. Neuropharmacology. 2013;69:82-8.
34. Cheng SH. Gene Therapy for the Neurological Manifestations in Lysosomal storage disorders. J Lipid Res. 2014;55(9):1827-38.
35. Simonato M et al. Progress in gene therapy for neurological disorders. Nat Rev Neurol. 2013;9(5):277-91.
36. Griffey M et al. Adeno-associated virus 2-mediated gene therapy decreases autofluorescent storage material and increases brain mass in a murine model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis. 2004;16(2):360-9.
37. Griffey M et al. AAV2-mediated ocular gene therapy for infantile neuronal ceroid lipofuscinosis. Mol Ther. 2005;12(3):413-21.
38. Griffey MA et al. CNS-directed AAV2-mediated gene therapy ameliorates functional deficits in a murine model of infantile neuronal ceroid lipofuscinosis. Mol Ther. 2006;13(3):538-47.
39. Sondhi D et al. AAV2-mediated CLN2 gene transfer to rodent and non-human primate brain results in long-term TPP-I expression compatible with therapy for LINCL. Gene Ther. 2005;12(22):1618-32.
40. Passini MA et al. Intracranial delivery of CLN2 reduces brain pathology in a mouse model of classical late infantile neuronal ceroid lipofuscinosis. J Neurosci. 2006;26(5):1334-42.
41. Sondhi D et al. Enhanced survival of the LINCL mouse following CLN2 gene transfer using the rh.10 rhesus macaque-derived adeno-associated virus vector. Mol Ther. 2007;15(3):481-91.
42. Sondhi D et al. Survival advantage of neonatal CNS gene transfer for late infantile neuronal ceroid lipofuscinosis. Exp Neurol. 2008;213(1):18-27.
43. Sondhi D et al. Long-term expression and safety of administration of AAVrh.10hCLN2 to the brain of rats and nonhuman primates for the treatment of late infantile neuronal ceroid lipofuscinosis. Hum Gene Ther Methods. 2012;23:324-335.
44. Macauley SL, Roberts MS, Wong AM, McSloy FB, Reddy AS, Cooper JD, Sands MS. Synergistic effects of CNS-directed gene therapy and bone marrow transplantation in the murine model of infantile neuronal ceroid lipofuscinosis. Ann Neurol. 2012;71(6):797-804.
45. Worgall S et al. Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA. Hum Gene Ther. 2008;19(5):463-74.
46. Roberts MS et al. Combination small molecule PPT1 mimetic and CNS-directed gene therapy as a treatment for infantile neuronal ceroid lipofuscinosis. J Inherit Metab Dis. 2012;35(5):847-57.
47. Wang Z et al. Rapid and highly efficient transduction by double-stranded adeno-associated virus vectors in vitro and in vivo. Gene Ther. 2003;10(26):2105-11.
48. McCarty DM et al. Adeno-associated virus terminal repeat (TR) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo. Gene Ther. 2003;10(26):2112-8.
49. Gray SJ et al. Preclinical differences of intravascular AAV9 delivery to neurons and glia: a comparative study of adult mice and nonhuman primates. Mol Ther. 2011;19(6):1058-69.
50. Federici T et al. Robust spinal motor neuron transduction following intrathecal delivery of AAV9 in pigs. Gene Ther. 2012;19(8):852-9.
51. Gadalla KK et al. Improved survival and reduced phenotypic severity following AAV9/MECP2 gene transfer to neonatal and juvenile male Mecp2 knockout mice. Mol Ther. 2013;21(1):18-30.
52. Ratko et al. Enzyme-replacement therapies for lysosomal storage diseases. U.S. Dept. Health and Human Services: Agency for Healthcare Research and Quality. 2013;12(13)-EHC154-EF.
53. Lu JY, Hu J, Hofmann SL. Human recombinant palmitoyl-protein thioesterase-1 (PPT1) for preclinical evaluation of enzyme replacement therapy for infantile neuronal ceroid lipofuscinosis. Mol Genet Metab. 2010;99(4):374-8.
54. Hu J et al. Intravenous high-dose enzyme replacement therapy with recombinant palmitoyl-protein thioesterase reduces visceral lysosomal storage and modestly prolongs survival in a preclinical mouse model of infantile neuronal ceroid lipofuscinosis. Mol Genet Metab. 2012;107(1-2):213-21.
55. Chang M et al. Intraventricular enzyme replacement improves disease phenotypes in a mouse model of late infantile neuronal ceroid lipofuscinosis. Mol Ther. 2008;16(4):649-56.
56. Meng Y et al. Systemic administration of tripeptidyl peptidase I in a mouse model of late infantile neuronal ceroid lipofuscinosis: effect of glycan modification. PLoS One. 2012;7(7):e40509.
57. Xu S et al. Large-volume intrathecal enzyme delivery increases survival of a mouse model of late infantile neuronal ceroid lipofuscinosis. Mol Ther. 2011;19(10):1842-8.
58. Vuillemenot BR et al. Recombinant human tripeptidyl peptidase-1 infusion to the monkey CNS: safety, pharmacokinetics, and distribution. Toxicol Appl Pharmacol. 2014;277(1):49-57.
59. Vuillemenot BR et al. Nonclinical evaluation of CNS-administered TPP1 enzyme replacement in canine CLN2 neuronal ceroid lipofuscinosis. Mol Genet Metab. 2014;114:281-93.
60. Meng Y et al. Effective intravenous therapy for neurodegenerative disease with a therapeutic enzyme and a peptide that mediates delivery to the brain. Mol Ther. 2014;22(3):547-53.
61. Lin L, Lobel P. Expression and analysis of CLN2 variants in CHO cells: Q100R represents a polymorphism, and G389E and R447H represent loss-of-function mutations. Hum Mutat. 2001;18(2):165.
62. Lin L, Lobel P. Production and characterization of recombinant human CLN2 protein for enzyme-replacement therapy in late infantile neuronal ceroid lipofuscinosis. Biochem J. 2001;357(Pt 1):49-55.
63. Kang TS, Stevens RC. Structural aspects of therapeutic enzymes to treat metabolic disorders. Hum Mutat. 2009;30(12):1591-610.
64. Boado RJ et al. Reversal of lysosomal storage in brain of adult MPS-I mice with intravenous Trojan horse-iduronidase fusion protein. Mol Pharm. 2011;8(4):1342-50.
65. Boado RJ, Pardridge WM. The Trojan Horse Liposome Technology for Nonviral Gene Transfer across the Blood-brain Barrier. J Drug Deliv. 2011;2011:296151.
66. Papademetriou J et al. Comparative binding, endocytosis, and biodistribution of antibodies and antibody-coated carriers for targeted delivery of lysosomal enzymes to ICAM-1 versus transferrin receptor. J Inherit Metab Dis. 2013;36(3):467-77.
67. Sorrentino NC et al. A highly secreted sulphamidase engineered to cross the blood-brain barrier corrects brain lesions of mice with mucopolysaccharidoses type IIIA. EMBO Mol Med. 2013;5(5):675-90.
68. Katz ML et al. Enzyme replacement therapy attenuates disease progression in a canine model of late-infantile neuronal ceroid lipofuscinosis (CLN2 disease). J Neurosci Res. 2014;92(11):1591-8.
69. Pardridge WM. Molecular Trojan horses for blood-brain barrier drug delivery. Discov Med. 2006;6(34):139-43.
70. Wang D et al. Engineering a lysosomal enzyme with a derivative of receptor-binding domain of apoE enables delivery across the blood-brain barrier. Proc Natl Acad Sci U S A. 2013;110(8):2999-3004.
71. Muro S. New biotechnological and nanomedicine strategies for treatment of lysosomal storage disorders. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2010;2(2):189-204.
72. Garnacho C et al. Delivery of acid sphingomyelinase in normal and niemann-pick disease mice using intercellular adhesion molecule-1-targeted polymer nanocarriers. J Pharmacol Exp Ther. 2008;325(2):400-8.
73. Papademetriou I et al. Combination-targeting to multiple endothelial cell adhesion molecules modulates binding, endocytosis, and in vivo biodistribution of drug nanocarriers and their therapeutic cargoes. J Control Release. 2014;188:87-98.
74. Ansari NH et al. Delivery of liposome-sequestered hydrophobic proteins to lysosomes of normal and Batten disease cells. J Neurosci Res. 1997;47(3):341-7.
75. Peters C et al. Hematopoietic cell transplantation for inherited metabolic diseases: an overview of outcomes and practice guidelines. Bone Marrow Transplant. 2003;31(4):229-39.
76. Malatack JJ, Consolini DM, Bayever E. The status of hematopoietic stem cell transplantation in lysosomal storage disease. Pediatr Neurol. 2003;29(5):391-403.
77. Wynn RF et al. Improved metabolic correction in patients with lysosomal storage disease treated with hematopoietic stem cell transplant compared with enzyme replacement therapy. J Pediatr. 2009;154(4):609-11.
78. Miller WP et al. Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. Blood. 2011;118(7):1971-8.
79. Poe MD, Chagnon SL, Escolar ML. Early treatment is associated with improved cognition in Hurler syndrome. Ann Neurol. 2014;76(5):747-53.
80. Chiu AY, Rao MS. Cell-based therapy for neural disorders - anticipating challenges. Neurotherapeutics. 2011;8(4):744-52.
81. Shihabuddin LS, Cheng SH. Neural stem cell transplantation as a therapeutic approach for treating lysosomal storage diseases. Neurotherapeutics. 2011;8(4):659-67.
82. Sidman RL et al. Injection of mouse and human neural stem cells into neonatal Niemann-Pick A model mice. Brain Res. 2007;1140:195-204.
83. Ahmad I et al. Neural stem cell implantation extends life in Niemann-Pick C1 mice. J Appl Genet. 2007;48(3):269-72.
84. Jeyakumar M et al. Neural stem cell transplantation benefits a monogenic neurometabolic disorder during the symptomatic phase of disease. Stem Cells. 2009;27(9):2362-70.
85. Tamaki SJ et al. Neuroprotection of host cells by human central nervous system stem cells in a mouse model of infantile neuronal ceroid lipofuscinosis. Cell Stem Cell. 2009;5(3):310-9.
86. Lee JM, Bae JS, Jin HK. Intracerebellar transplantation of neural stem cells into mice with neurodegeneration improves neuronal networks with functional synaptic transmission. J Vet Med Sci. 2010;72(8):999-1009.
87. Neri M et al. Neural stem cell gene therapy ameliorates pathology and function in a mouse model of globoid cell leukodystrophy. Stem Cells. 2011;29(10):1559-71.
88. Arthur JR et al. Therapeutic effects of stem cells and substrate reduction in juvenile Sandhoff mice. Neurochem Res. 2012;37(6):1335-43.
89. Kim SU. Lysosomal storage diseases: Stem cell-based cell- and gene-therapy. Cell Transplant. 2014. [Epub ahead of print].
90. Lee JP et al. Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease. Nat Med. 2007;13(4):439-47.
91. Selden NR et al. Central nervous system stem cell transplantation for children with neuronal ceroid lipofuscinosis. J Neurosurg Pediatr. 2013;11(6):643-52.
92. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663-76.
93. Robinton DA, Daley GQ. The promise of induced pluripotent stem cells in research and therapy. Nature. 2012;481(7381):295-305.
94. Hanna J et al. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science. 2007;318(5858):1920-3.
95. Wernig M et al. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease. Proc Natl Acad Sci U S A. 2008;105(15):5856-61.
96. Lu X, Zhao T. Clinical therapy using iPSCs: hopes and challenges. Genomics Proteomics Bioinformatics. 2013;11(5):294-8.
97. Keeling KM et al. Gentamicin-mediated suppression of Hurler syndrome stop mutations restores a low level of alpha-L-iduronidase activity and reduces lysosomal glycosaminoglycan accumulation. Hum Mol Genet. 2001;10(3):291-9.
98. Sleat DE et al. Aminoglycoside-mediated suppression of nonsense mutations in late infantile neuronal ceroid lipofuscinosis. Eur J Paediatr Neurol. 2001;5(Suppl A):57-62.
99. Hein LK et al. alpha-L-iduronidase premature stop codons and potential read-through in mucopolysaccharidosis type I patients. J Mol Biol. 2004;338(3):453-62.
100. Zingman LV et al. Aminoglycoside-induced translational read-through in disease: overcoming nonsense mutations by pharmacogenetic therapy. Clin Pharmacol Ther. 2007;81(1):99-103.
101. Rodriguez-Pascau L et al. Antisense oligonucleotide treatment for a pseudoexon-generating mutation in the NPC1 gene causing Niemann-Pick type C disease. Hum Mutat. 2009;30(11):E993-1001.
102. Sarkar C, Zhang Z, Mukherjee AB. Stop codon read-through with PTC124 induces palmitoyl-protein thioesterase-1 activity, reduces thioester load and suppresses apoptosis in cultured cells from INCL patients. Mol Genet Metab. 2011;104(3):338-45.
103. Rigo F et al. Antisense-based therapy for the treatment of spinal muscular atrophy. J Cell Biol. 2012;199(1):21-5.
104. Wang D et al. The designer aminoglycoside NB84 significantly reduces glycosaminoglycan accumulation associated with MPS I-H in the Idua-W392X mouse. Mol Genet Metab. 2012;105(1):116-25.
105. Havens MA, Duelli DM, Hastings ML. Targeting RNA splicing for disease therapy. Wiley Interdiscip Rev RNA. 2013;4(3):247-66.
106. Keeling KM et al. Attenuation of nonsense-mediated mRNA decay enhances in vivo nonsense suppression. PLoS One. 2013;8(4):e60478.
107. Miller JN, Chan CH, Pearce DA. The role of nonsense-mediated decay in neuronal ceroid lipofuscinosis. Hum Mol Genet. 2013;22(13):2723-34.
108. Miller JN, Kovacs AD, Pearce DA. The novel Cln1R151X mouse model of infantile neuronal ceroid lipofuscinosis (INCL) for testing nonsense suppression therapy. Hum Mol Genet. 2014;24:185-96.
109. Miller JN, Pearce DA. Nonsense-mediated decay in genetic disease: friend or foe? Mutat Res Rev Mutat Res. 2014;762:52-64.
110. Rigo F, Seth PP, Bennett CF. Antisense oligonucleotide-based therapies for diseases caused by pre-mRNA processing defects. Adv Exp Med Biol. 2014;825:303-52.
111. Siva K, Covello G, Denti MA. Exon-skipping antisense oligonucleotides to correct missplicing in neurogenetic diseases. Nucleic Acid Ther. 2014;24(1):69-86.
112. Finkel RS et al. Phase 2a study of ataluren-mediated dystrophin production in patients with nonsense mutation Duchenne muscular dystrophy. PLoS One. 2013;8(12):e81302.
113. Kerem E et al. Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet. 2008;372(9640):719-27.
114. Brooks DA, Muller VJ, Hopwood JJ. Stop-codon read-through for patients affected by a lysosomal storage disorder. Trends Mol Med. 2006;12(8):367-73.
115. Hirawat S et al. Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers. J Clin Pharmacol. 2007;47(4):430-44.
116. Kole R, Krainer AR, Altman S. RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nat Rev Drug Discov. 2012;11(2):125-40.
117. Lentz JJ et al. Rescue of hearing and vestibular function by antisense oligonucleotides in a mouse model of human deafness. Nat Med. 2013;19(3):345-50.
118. Popp MW, Maquat LE. The dharma of nonsense-mediated mRNA decay in mammalian cells. Mol Cells. 2014;37(1):1-8.
119. Schweingruber C et al. Nonsense-mediated mRNA decay - mechanisms of substrate mRNA recognition and degradation in mammalian cells. Biochim Biophys Acta. 2013;1829(6-7):612-23.
120. Huang L, Wilkinson MF. Regulation of nonsense-mediated mRNA decay. Wiley Interdiscip Rev RNA. 2012;3(6):807-28.
121. Nomakuchi TT et al. Antisense oligonucleotide-directed inhibition of nonsense-mediated mRNA decay. Nat Biotechnol. 2015;34:164-6.
122. Glass CK et al. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140(6):918-34.
123. Killedar S et al. Mucopolysaccharidosis IIIB, a lysosomal storage disease, triggers a pathogenic CNS autoimmune response. J Neuroinflammation. 2010;7:39.
124. Schultz ML et al. Clarifying lysosomal storage diseases. Trends Neurosci. 2011;34(8):401-10.
125. Vitner EB et al. Contribution of brain inflammation to neuronal cell death in neuronopathic forms of Gaucher's disease. Brain. 2012;135(Pt 6):1724-35.
126. Parente MK et al. Dysregulation of gene expression in a lysosomal storage disease varies between brain regions implicating unexpected mechanisms of neuropathology. PLoS One. 2012;7(3):e32419.
127. Abo-Ouf H et al. Deletion of tumor necrosis factor-alpha ameliorates neurodegeneration in Sandhoff disease mice. Hum Mol Genet. 2013;22(19):3960-75.
128. Archer LD et al. Mucopolysaccharide diseases: a complex interplay between neuroinflammation, microglial activation and adaptive immunity. J Inherit Metab Dis. 2014;37(1):1-12.
129. Cologna SM et al. Human and mouse neuroinflammation markers in Niemann-Pick disease, type C1. J Inherit Metab Dis. 2014;37(1):83-92.
130. Groh J et al. Immune cells perturb axons and impair neuronal survival in a mouse model of infantile neuronal ceroid lipofuscinosis. Brain. 2013;136(Pt 4):1083-101.
131. Bible E et al. Regional and cellular neuropathology in the palmitoyl protein thioesterase-1 null mutant mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis. 2004;16(2):346-59.
132. Cooper JD. Progress towards understanding the neurobiology of Batten disease or neuronal ceroid lipofuscinosis. Curr Opin Neurol. 2003;16(2):121-8.
133. Brooks AI et al. Functional categorization of gene expression changes in the cerebellum of a Cln3-knockout mouse model for Batten disease. Mol Genet Metab. 2003;78(1):17-30.
134. Burkovetskaya M et al. Evidence for aberrant astrocyte hemichannel activity in Juvenile Neuronal Ceroid Lipofuscinosis (JNCL). PLoS One. 2014;9(4):e95023.
135. Jalanko A et al. Mice with Ppt1Dex4 mutation replicate the INCL phenotype and show an inflammation-associated loss of interneurons. Neurobiol Dis. 2013;18:226-41.
136. Kay GW, Palmer DN. Chronic oral administration of minocycline to sheep with ovine CLN6 neuronal ceroid lipofuscinosis maintains pharmacological concentrations in the brain but does not suppress neuroinflammation or disease progression. J Neuroinflammation. 2013;10:97.
137. Kay GW et al. Activation of non-neuronal cells within the prenatal developing brain of sheep with neuronal ceroid lipofuscinosis. Brain Pathol. 2006;16(2):110-6.
138. Kielar C et al. Molecular correlates of axonal and synaptic pathology in mouse models of Batten disease. Hum Mol Genet. 2009;18(21):4066-80.
139. Lim MJ et al. IgG entry and deposition are components of the neuroimmune response in Batten disease. Neurobiol Dis. 2007;25(2):239-51.
140. Macauley SL, Pekny M, Sands MS. The role of attenuated astrocyte activation in infantile neuronal ceroid lipofuscinosis. J Neurosci. 2011;31(43):15575-85.
141. Macauley SL et al. Cerebellar pathology and motor deficits in the palmitoyl protein thioesterase 1-deficient mouse. Exp Neurol. 2009;217(1):124-35.
142. Macauley SL et al. An anti-neuroinflammatory that targets dysregulated glia enhances the efficacy of CNS-directed gene therapy in murine infantile neuronal ceroid lipofuscinosis. J Neurosci. 2014;34(39):13077-82.
143. Kielar C et al. Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis. 2007;25(1):150-62.
144. Seehafer SS et al. Immunosuppression alters disease severity in juvenile Batten disease mice. J Neuroimmunol. 2011;230(1-2):169-72.
145. Qiao X, Lu JY, Hofmann SL. Gene expression profiling in a mouse model of infantile neuronal ceroid lipofuscinosis reveals upregulation of immediate early genes and mediators of the inflammatory response. BMC Neurosci. 2007;8:95.
146. Weimer JM et al. Alterations in striatal dopamine catabolism precede loss of substantia nigra neurons in a mouse model of juvenile neuronal ceroid lipofuscinosis. Brain Res. 2007;1162:98-112.
147. Weimer JM et al. Cerebellar defects in a mouse model of juvenile neuronal ceroid lipofuscinosis. Brain Res. 2009;1266:93-107.
148. Jalanko A et al. Mice with Ppt1Deltaex4 mutation replicate the INCL phenotype and show an inflammation-associated loss of interneurons. Neurobiol Dis. 2005;18(1):226-41.
149. Macauley SL, Sands MS. Promising CNS-directed enzyme replacement therapy for lysosomal storage diseases. Exp Neurol. 2009;218(1):5-8.
150. Tyynela J et al. Hippocampal pathology in the human neuronal ceroid-lipofuscinoses: distinct patterns of storage deposition, neurodegeneration and glial activation. Brain Pathol. 2004;14(4):349-57.
151. Mahmood F et al. A zebrafish model of CLN2 disease is deficient in tripeptidyl peptidase 1 and displays progressive neurodegeneration accompanied by a reduction in proliferation. Brain. 2013;136(Pt 5):1488-507.
152. Mole SE, Williams RE, Goebel HH. The neuronal ceroid lipofuscinoses (Batten disease). 2nd ed. Oxford: Oxford University Press; 2011. p. 444.
153. Kopra O et al. A mouse model for Finnish variant late infantile neuronal ceroid lipofuscinosis, CLN5, reveals neuropathology associated with early aging. Hum Mol Genet. 2004;13(23):2893-906.
154. von Schantz C et al. Brain gene expression profiles of Cln1 and Cln5 deficient mice unravels common molecular pathways underlying neuronal degeneration in NCL diseases. BMC Genomics. 2008;9:146.
155. Sardiello M et al. A gene network regulating lysosomal biogenesis and function. Science. 2009;325(5939):473-7.
156. Palmieri M et al. Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. Hum Mol Genet. 2011;20(19):3852-66.
157. Medina DL et al. Transcriptional activation of lysosomal exocytosis promotes cellular clearance. Dev Cell. 2011;21(3):421-30.
158. Feeney EJ et al. What else is in store for autophagy? Exocytosis of autolysosomes as a mechanism of TFEB-mediated cellular clearance in Pompe disease. Autophagy. 2013;9(7):1117-8.
159. Song W et al. TFEB regulates lysosomal proteostasis. Hum Mol Genet. 2013;22(10):1994-2009.
160. Spampanato C et al. Transcription factor EB (TFEB) is a new therapeutic target for Pompe disease. EMBO Mol Med. 2013;5(5):691-706.
161. Song W et al. 2-Hydroxypropyl-beta-cyclodextrin promotes transcription factor EB-mediated activation of autophagy: implications for therapy. J Biol Chem. 2014;289(14):10211-22.
162. Moskot M et al. The phytoestrogen genistein modulates lysosomal metabolism and transcription factor EB (TFEB) activation. J Biol Chem. 2014;289(24):17054-69.
163. Xu M et al. delta-Tocopherol reduces lipid accumulation in Niemann-Pick type C1 and Wolman cholesterol storage disorders. J Biol Chem. 2012;287(47):39349-60.
164. Benedict JW et al. Protein product of CLN6 gene responsible for variant late-onset infantile neuronal ceroid lipofuscinosis interacts with CRMP-2. J Neurosci Res. 2009;87(9):2157-66.
165. Hensley K et al. Collapsin response mediator protein-2: an emerging pathologic feature and therapeutic target for neurodisease indications. Mol Neurobiol. 2011;43(3):180-91.
166. Khanna R et al. Opening Pandora's jar: a primer on the putative roles of CRMP2 in a panoply of neurodegenerative, sensory and motor neuron, and central disorders. Future Neurol. 2012;7(6):749-71.
167. Hensley K et al. Proteomic identification of binding partners for the brain metabolite lanthionine ketimine (LK) and documentation of LK effects on microglia and motoneuron cell cultures. J Neurosci. 2010;30(8):2979-88.
168. Hensley K, Venkova K, Christov A. Emerging biological importance of central nervous system lanthionines. Molecules. 2010;15(8):5581-94.
169. Nada SE et al. A derivative of the CRMP2 binding compound lanthionine ketimine provides neuroprotection in a mouse model of cerebral ischemia. Neurochem Int. 2012;61(8):1357-63.
170. Hubbard C et al. Lanthionine ketimine ethyl ester partially rescues neurodevelopmental defects in unc-33 (DPYSL2/CRMP2) mutants. J Neurosci Res. 2013;91(9):1183-90.
171. Beyreuther BK et al. Lacosamide: a review of preclinical properties. CNS Drug Rev. 2007;13(1):21-42.
172. Curia G et al. Lacosamide: a new approach to target voltage-gated sodium currents in epileptic disorders. CNS Drugs. 2009;23(7):555-68.
173. Sarkar C et al. Neuroprotection and lifespan extension in Ppt1(-/-) mice by NtBuHA: therapeutic implications for INCL. Nat Neurosci. 2013;16(11):1608-17.
174. Zhang Z et al. Lysosomal ceroid depletion by drugs: therapeutic implications for a hereditary neurodegenerative disease of childhood. Nat Med. 2001;7(4):478-84.
175. Bavarsad Shahripour R, Harrigan MR, Alexandrov AV. N-acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities. Brain Behav. 2014;4(2):108-22.
176. Levin SW et al. Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study. Lancet Neurol. 2014;13(8):777-87.
177. Zheng W et al. Three classes of glucocerebrosidase inhibitors identified by quantitative high-throughput screening are chaperone leads for Gaucher disease. Proc Natl Acad Sci U S A. 2007;104(32):13192-7.
178. Geng H et al. Novel patient cell-based HTS assay for identification of small molecules for a lysosomal storage disease. PLoS One. 2011;6(12):e29504.
179. Ribbens J et al. A high-throughput screening assay using Krabbe disease patient cells. Anal Biochem. 2013;434(1):15-25.
180. Griffin JL et al. Vitamin E deficiency and metabolic deficits in neuronal ceroid lipofuscinosis described by bioinformatics. Physiol Genomics. 2002;11(3):195-203.
181. Yoon DH et al. Protective potential of resveratrol against oxidative stress and apoptosis in Batten disease lymphoblast cells. Biochem Biophys Res Commun. 2011;414(1):49-52.
182. Wei H et al. Disruption of adaptive energy metabolism and elevated ribosomal p-S6K1 levels contribute to INCL pathogenesis: partial rescue by resveratrol. Hum Mol Genet. 2011;20(6):1111-21.
183. Saha A et al. The blood-brain barrier is disrupted in a mouse model of infantile neuronal ceroid lipofuscinosis: amelioration by resveratrol. Hum Mol Genet. 2012;21(10):2233-44.
184. Wei H et al. ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative lysosomal storage disorders and are alleviated by chemical chaperones. Hum Mol Genet. 2008;17(4):469-77.
185. Landis SC et al. A call for transparent reporting to optimize the predictive value of preclinical research. Nature. 2012;490(7419):187-91.